Gastric bypass surgery (GB) and sleeve gastrectomy induce diabetes remission immediately after surgery. Patients after GB have earlier and higher peak, and lower nadir, glucose levels along with larger insulin and gut hormone, glucagon like-peptide 1 (GLP-1) and glucose dependent insulinotropic peptide (GIP), response to meal ingestion. The weight-independent glycemic effect of GB has been attributed to increase in enteroinsular- axis activity (incretin effect) and altered glucose flux. While the glycemic effectsof GB is exaggerated in a subset of subjects with a devastating late-complication of hyperinsulinemia hypoglycemia syndrome, these changes are smaller after SG compared to GB, suggestive of a continuum in alteration in islet function. It has been recognized that GLP-1-stimulated postprandial insulin secretion is larger after GB, and especially so in individuals with the GB-related hypoglycemia. However, the effects of GIP or non-hormonal components of the enteroinsular axis (i.e., nutrient and neural -mainly parasympathetic nervous system [PNS]- stimulation) on insulin secretion after GB are completely unknown, as is the role of enteroinsular axis activity after SG. Meal ingestion increases insulin secretion during hypoglycemia in GB subjects; but it is unknown whether meal- induced -cell secretion in this setting is due the glucose-independent actions of GLP-1, or to increased PNS activity, or direct nutrient effect. Our main hypothesis is that the improved glycemic effects of GB and SG are due to variation in the effect of incretins (GLP-1 and GIP) and PNS activity on insulin secretion independent of macronutrient composition or glycemic levels. We also hypothesize that enhanced enteroinsular activity on islet function are greater in subjects with post-GB hypoglycemia than in those without. To test our hypothesis we will: 1) Identify the contribution of GLP-1 and GIP to the incretin-mediated islet cell response to glucose and protein ingestion after GB or SG. We hypothesize that postprandial -cell effects of endogenous GLP-1 and GIP are larger after GB, especially in those with hypoglycemia, and after SG compared to the non-surgical controls during both glucose and protein challenges. 2) Determine the contribution of GLP-1 and parasympathetic activity to islet cell function during hypoglycemic clamp after meal ingestion in individuals after GB or SG. We hypothesize that the contribution of neural and hormonal aspects of enteroinsular activity (i.e., PNS activity and GLP-1 action) to postprandial -cell output in this setting will be larger in subjects after GB compared to those after SG and non-surgical controls. Patients with GB-related hypoglycemia, asymptomatic GB and SG individuals, and matched non-operated controls will be studied. To determine the glycemic effects of GB mediated by altered glucose flux, a fifth group of non-operated subjects will receive glucose intraduodenally simulating the rate of glucose flux after GB in Aim 1. This project will carefully characterize the effects of a long-lasting restructured GI tract as a result of GB or SG on islet cell function, and how manipulation of enteroinsular-axis activity can be utilized for therapeutic and preventive purposes.